ENST00000652248.1:n.*168-4817C>G – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000652248.1(ENSG00000286070):n.*168-4817C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 150,638 control chromosomes in the GnomAD database, including 8,307 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.33 ( 8307 hom., cov: 31)

Exomes 𝑓: 0.045 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

ENSG00000286070
ENST00000652248.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.384

Publications

19 publications found

Variant links:

Genes affected

ENSG00000286070 (HGNC:):

ENSG00000286070 links:

GGT1 (HGNC:4250): (gamma-glutamyltransferase 1) The enzyme encoded by this gene is a type I gamma-glutamyltransferase that catalyzes the transfer of the glutamyl moiety of glutathione to a variety of amino acids and dipeptide acceptors. The enzyme is composed of a heavy chain and a light chain, which are derived from a single precursor protein. It is expressed in tissues involved in absorption and secretion and may contribute to the etiology of diabetes and other metabolic disorders. Multiple alternatively spliced variants have been identified. There are a number of related genes present on chromosomes 20 and 22, and putative pseudogenes for this gene on chromosomes 2, 13, and 22. [provided by RefSeq, Jan 2014]

GGT1 Gene-Disease associations (from GenCC):

gamma-glutamyl transpeptidase deficiency
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics

GGT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
GGT1	NM_013430.3 link	c.-428-4817C>G	intron_variant	Intron 1 of 15		NP_038347.2	P19440-1A0A140VJJ9
GGT1	NM_001288833.2 link	c.-819C>G	upstream_gene_variant		ENST00000400382.6	NP_001275762.1	P19440-1A0A140VJJ9
GGT1	NM_013421.3 link	c.-747C>G	upstream_gene_variant			NP_038265.2	P19440-1A0A140VJJ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000286070	ENST00000652248.1 link	n.*168-4817C>G		intron_variant	Intron 5 of 19			ENSP00000499210.1
GGT1	ENST00000400382.6 link	c.-819C>G		upstream_gene_variant		2	NM_001288833.2	ENSP00000383232.1		P19440-1

Frequencies

GnomAD3 genomes

AF:

0.325

AC:

48970

AN:

150520

Hom.:

8299

Cov.:

show subpopulations

Gnomad AFR

AF:

0.232

Gnomad AMI

AF:

0.261

Gnomad AMR

AF:

0.424

Gnomad ASJ

AF:

0.423

Gnomad EAS

AF:

0.360

Gnomad SAS

AF:

0.266

Gnomad FIN

AF:

0.305

Gnomad MID

AF:

0.467

Gnomad NFE

AF:

0.359

Gnomad OTH

AF:

0.368

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0448

AC:

AN:

134

Hom.:

Cov.:

AF XY:

0.0566

AC XY:

AN XY:

106

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0455

AC:

AN:

110

Other (OTH)

AF:

0.167

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.054799), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.325

AC:

48996

AN:

150638

Hom.:

8307

Cov.:

AF XY:

0.322

AC XY:

23648

AN XY:

73532

show subpopulations

African (AFR)

AF:

0.232

AC:

9548

AN:

41194

American (AMR)

AF:

0.424

AC:

6417

AN:

15118

Ashkenazi Jewish (ASJ)

AF:

0.423

AC:

1457

AN:

3448

East Asian (EAS)

AF:

0.360

AC:

1825

AN:

5066

South Asian (SAS)

AF:

0.267

AC:

1277

AN:

4782

European-Finnish (FIN)

AF:

0.305

AC:

3155

AN:

10332

Middle Eastern (MID)

AF:

0.475

AC:

135

AN:

284

European-Non Finnish (NFE)

AF:

0.359

AC:

24186

AN:

67428

Other (OTH)

AF:

0.365

AC:

761

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

1501

3002

4502

6003

7504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

482

964

1446

1928

2410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.162

Hom.:

302

Asia WGS

AF:

0.324

AC:

1121

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

8.0

(source)

DANN

Benign

0.36

PhyloP100

0.38

PromoterAI

0.088

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over